All ETDs from UAB

Advisory Committee Chair

Lynn Dobrunz

Advisory Committee Members

Scott Wilson

Candace Floyd

Robin Lester

Lori L McMahon

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


The ubiquitin proteasome system (UPS) is a coordinated process by which the cell can control protein distribution and abundance. Proteins are marked for turnover by the construction of a polyubiquitin chain on the protein substrate. Once engaged by the proteasome, the ubiquitin side-chain is disassembled by proteasomal deubiquitinating enzymes (DUBs), preventing entry of ubiquitin into the proteasome and recycling it for use in future reactions. One of the DUBs that resides on the proteasome is Ubiquitin Specific Protease 14 (Usp14), which is mutated in the ataxia (axJ) mice. This mutation results in pronounced physical deficits and, unexpectedly, a deficit in hippocampal synaptic function. This deficit in the hippocampus was primarily characterized as a reduction in paired pulse facilitation (PPF), a form of synaptic short-term plasticity. The purpose of this project was to understand how the proteasome is able to modulate PPF. To this end we found that the deficit in PPF is due to an increase in the rate of degradation at the proteasome. This change results from the loss of Usp14's ability to regulate the proteasome, independent of Usp14's ability to process ubiquitin chains. Surprisingly, the deficit in PPF is not caused by a change in the initial synaptic release probability. Instead, an increased rate of proteasomal degradation results in a significant reduction in the number of docked vesicles at the synaptic terminal. This deficit, combined with a hypothesized homeostatic increase in the release probability per vesicle, accounts for the observed deficit in PPF of the axJ mice.



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